Thioacetalation and Multi-Component Thiomethylative Friedel-Crafts Arylation Using BF3SMe2

Herein, a method for thioacetalation using BF3SMe2 is presented. The method allows for convenient and odor-free transformation of aldehydes to methyl-dithioacetals, a simple but sparsely reported structural moiety, in good yields with a diverse set of aromatic aldehydes. In addition, a thiomethylative Friedel-Crafts reaction was discovered, affording thiomethylated diarylmethanes in good to excellent yields. The resulting diarylmethane core is of interest as it is found in many biologically active compounds, and its utility is further demonstrated as a novel precursor to unsymmetrical triarylmethanes. This work also highlights the usefulness and the synthetic capabilities of the readily available reagent BF3SMe2 beyond its reactivity profile as a dealkylation reagent.


■ INTRODUCTION
Boron trifluoride etherate is a commonly employed reagent in organic synthesis due to its combination of powerful Lewis acidity and ease of handling. 1−5 In contrast, the related sulfur analogue boron trifluoride dimethyl sulfide (BF 3 SMe 2 ) has received considerably less attention. Perhaps the most wellknown and earliest reported use of this system is benzyl group cleavage 6 using a combination of boron trifluoride etherate and dimethyl sulfide. The combined boron trifluoride complex has since been used almost exclusively for ether dealkylations. 7−18 Some developments toward uses of the complex have nonetheless been accomplished, such as selective cleavage of di-tertbutylsilylene ethers, 19 selective methoxy cleavage, 20 and as a borylation reagent. 21 Recently, we reported BF 3 SMe 2 as a convenient thiomethylating reagent and also showed that it could reduce nitro groups in certain substrates. 22 During our investigation, we also found that BF 3 SMe 2 could produce methyl-dithioacetals from aldehydes albeit in a single example and in low yield.
Thioacetals are the sulfur analogue of the acetal group and are often employed as protecting groups to mask the electrophilic carbon of aldehydes and ketones as they offer increased acid stability. 23 In addition to carbonyl protection, the thioacetal group can also be employed as a synthetic handle for other transformations and the most well-known example is the Corey−Seebach umpolung reaction. 24,25 Generally, thioacetals are prepared via the Lewis acid (ZnCl 2 , 26 BF 3 etherate, 27 AlCl 3 , 28 and TiCl 4 29 ) catalyzed addition of thiols to aldehydes and ketones. Thioacetals can also be accessed from other functional groups such as olefins, 30 acetals, 31,32 or propargylic carbons. 33 Due to the odorous nature of thiols, there have been numerous efforts toward alleviation of this issue. Methods using solid-supported thioacetalation reagents have been reported 34,35 as well as diacetyl ketene dithioacetals 36−38 and derivatives thereof 39−41 for achieving thioacetalation in odorless conditions. However, these methods are limited to cyclic thioacetals and require tedious preparation of the thioacetalating agents.
Advances have also been made in the field of thioacetalation, and there have been mild catalytic methods developed. 31,42−52 However, despite being the structurally simplest thioacetal derivative, methyl dithioacetals are not found in these examples, most likely due to the highly odorous nature of methanethiol. Besides methanethiol, there are also methods utilizing dimethyldislufide 53−55 to achieve methyl dithioacetals, although an unpleasant odor is associated with this reagent as well. There are examples that avoid this problem by using methylthiotrimethylsilane, 56−61 although additional additives are often required and the reagent is rather expensive (Scheme 1).
Due to the usefulness of dithioacetals as a synthetic moiety in organic chemistry and the lack of convenient methods to access methyl dithioacetals, we set out to investigate the use of BF 3 SMe 2 as a methyl-dithioacetalation reagent. We envisaged a convenient, odor-free method that would further broaden the utility of BF 3 SMe 2 as a reagent in organic chemistry.

■ RESULTS AND DISCUSSION
We began our investigation by screening reaction conditions using 2-napthaldehyde (1a) as the model substrate (Table 1).
Initial attempts found that using 2 equiv of BF 3 SMe 2 (2 mmol) at 60°C resulted in 37% of the target dithioacetal 1b. It was also noted that concentration was important, as increasing the volume of solvent from 1 mL to 5 mL reduced the yield significantly to 10% (entry 2). Next, the effects of temperature were investigated, and we found that 80°C increased the yield to 44% while increasing it further to 100°C was detrimental and only traces of the product could be detected (LCMS analysis). With the optimal temperature found, we continued by increasing the amount of BF 3 SMe 2 , and gratifyingly 3 equiv increased the yield to 60%. Increasing the amount further to 4 equiv increased the yield to 68%, while 5 equiv only gave a slight increase of 71%, so 4 equiv was selected for further investigation. Lastly, increasing the reaction time did not give any further improvement, and control experiments removing the Lewis acid (entry 9) or using catalytic amounts of BF 3 OEt 2 (entry 10) gave no observed reaction.
With suitable conditions in hand, the scope and limitations of the method were investigated (Table 2). Benzaldehyde and 4phenylbenzaldehyde gave thioacetals 2b and 3b in moderate to good yield as did the halogenated substrates 4-chloro-and 4fluorobenzaldehyde. Interestingly, 4-bromobenzaldehyde afforded the thiomethyl substituted product 6b, while 3bromobenzaldehyde returned the expected thioacetal product 7b in good yield. This observation might be explained by aldehyde activation by BF 3 , followed by a Br abstraction by DMS (soft nucleophile/soft base), 62 and attack on the formed DMS-Br complex (Scheme S1, the SI). Electron-poor aromatics quinoline-3-carboxaldehyde and 2-pyridinecarboxaldehyde reacted smoothly to give the desired thioacetals in good yields. More electron-rich aldehydes resulted in low to moderate yields, where 4-(p-tolyloxy)benzaldehyde formed a stable dimethylsulfonium derivative as an additional product (12ba, SI). We believe that this transformation occurs via a DMS-mediated reduction, 22 followed by a nucleophilic attack from an additional DMS molecule (Scheme S2, SI). Furthermore, 4-phenoxybenzaldehyde also afforded additional di-and trimeric products presumably resulting from substitution of a thiomethyl group at the 4-position of the electron-rich phenoxyether moiety. Notably, N-(4-formylphenyl)acetamide and 4-formylbenzoic  acid were compatible with the method, although 14b resulted in lower yield due to troublesome purification. Finally, 2phenylbenzaldehyde underwent concomitant thiomethylation and cyclization to afford the thiomethyl fluorene derivative 15b in 79% yield. Attempts to extend the method to aliphatic aldehydes and ketones were unfortunately unsuccessful.
Intrigued by the cyclization of 2-biphenylaldehyde, and the apparent polymerization of 4-phenoxybenzaldehyde, we decided to investigate if the developed conditions could be utilized for cascade thiomethylation/arylation reactions. A literature survey revealed that, indeed, similar reactions have been described before. 63,64 However, these methods proceed via the use of odorous ethanethiol, and to the best of our knowledge, the use of a thiomethyl source in this context is unprecedented.
Arylmethanes are of considerable medicinal interest ( Figure  1) and can for example be found in central nervous system stimulants modafinil and CRL-40,940, 65,66 anti-seizure medication phenytoin, 67 liarozole, 68 a retinoic acid metabolismblocking agent, the anti-diabetic imirestat, 69 and CDRI-830, with anti-tubercular activity. 70 The structures are also useful for the synthesis of dyes, here exemplified with crystal violet, a compound that is utilized for staining of bacteria, 71 DNA, 72 proteins, 73 and also exhibits antibacterial properties. 74 With the aim of developing a metal-free cascade thiomethylation/arylation sequence, we set out to explore the possibility of using BF 3 SMe 2 as a dual-function Lewis acid and non-odorous sulfur source.
As a model substrate, N,N-dimethylaniline (1c) was chosen as the nucleophile, with benzaldehyde (2a) as the electrophile (Table 3). First, we explored the optimal amount of BF 3 SMe 2 and, to our delight, 2 equivalents at 80°C gave 79% of the desired product. Increasing the equivalents to 4 resulted in an improved 89% yield, while increasing it further was not beneficial and decreased the yield slightly (entries 1−3). We also found that increasing the amount of aniline or running the reaction in neat conditions gave no increase in yield (entries 4− 5). Finally, reducing the reaction temperature to 60°C resulted in a low yield of 1d (entry 6) along with alcohol 1e (27%) and triarylmethane 1f (22%) side products ( Figure 2).
With suitable conditions in hand, we continued exploring the scope of the reaction ( Table 4). The substituted anilines N,Ndiethylaniline and N-methyl-4-phenylpiperazine reacted smoothly resulting in products 2d and 3d in good yield.
Halogenated anilines were also well tolerated, affording products 4-6d in good to excellent yields. 2-Bromo-N,Ndimethylaniline was found to be less reactive, but this could be overcome by switching to solvent-free conditions. Methyl phenyl sulfide also reacted smoothly, although a longer 48 h reaction time was required to reach completion. The conditions were also compatible with diphenyl ether, which gave the bisether product 8d, in 32% yield. Our attempts to expand the scope to indoles revealed that these nucleophiles were too reactive and, instead of the target thiomethylated product, resulted in the exclusive formation of bis(indolyl)methanes. This was observed despite efforts to reduce reaction temperature and time.
Next, we turned our attention to exploring the aldehyde component and 2-napthaldehyde, 4-methylbenzaldehyde, and 4-phenylbenzaldehyde afforded the desired products 9-11d in good yields. Electron-withdrawing groups such as 4-(trifluoromethyl) and 4-(methylsulfonyl) were well tolerated, as were the electron donating 4-(methylthio) and 4-(dimethylamino) groups. In the case of 4-(dimethylamino)benzaldehyde, lower reactivity was observed, and again, neat conditions could be used to increase the yield. Halogen groups were also well tolerated as can be seen in the formation of compounds 16-18d. Finally, 1,3dibenzaldehyde returned the bis-diarylmethane product 20d in good yield. The reaction was also scalable, where performing a 5 mmol reaction of benzaldehyde and N,N-dimethylaniline resulted only in a slightly reduced yield of 1d (84%).
We then set out to clarify the reaction mechanism for the transformation, and two suggested pathways are presented in Scheme 2. In path A, the dithioacetal is formed first, followed by the formation of the thionium ion(I), and a final Friedel-Crafts type arylation leads to the product. In the second pathway (B), the order of events is reversed with an initial Lewis acid promoted Friedel-Crafts reaction followed by substitution of the activated alcohol(III) and a final demethylation, possibly by the   eliminated oxygen 75 or an additional SMe 2 , 6 to afford the product.
To determine which pathway was more plausible, a set of control reactions were performed (Table 5). First, we reacted dithioacetal 2b with dimethylaniline in the presence of 4 equiv of BF 3 OEt 2 at 80°C. This reaction was rather sluggish, and only 30% of the desired product was isolated (entry 1). We then went on to react benzaldehyde in the absence of a sulfur source, and this resulted in the triarylmethane product (1f) in 42% yield. When the amount of aniline was increased to 3 equivalents, the triarylmethane product was isolated in 92% yield (entries 2−3).  Table 5. Mechanistic Investigation a Isolated yield. b 1.1 equiv 1c c 3 equiv 1c d In the absence of 1c.

Scheme 2. Proposed Pathways for the Thiomethylative Friedel-Crafts Arylation Reaction
Next, when using the putative alcohol intermediate 1e as a substrate, the desired product was isolated in 88% yield (entry 4). Taken together, these findings support the direct Friedel-Crafts pathway (Path B), where attack of aniline is favored over thioacetal formation and is most likely the first step in the reaction. The thioacetal pathway cannot be ruled out as the reaction still proceeds via this intermediate, albeit to a lesser extent.
During our mechanistic investigations, we noted that displacement of the thiomethyl group occurred upon exposure of 1d to nucleophiles in certain conditions. We, therefore, reasoned that it could be utilized as a latent handle for further synthesis. After some experimentation, we found that the thiomethyl group was readily substituted under acidic conditions (Scheme 3) in the presence of arene nucleophiles.

■ CONCLUSIONS
In summary, our efforts to explore BF 3 SMe 2 as a versatile and underutilized reagent have resulted in the development of two new thiomethylation reactions. First, the synthesis of methyl dithioacetals from aldehydes has been demonstrated, avoiding odorous methanethiol and expanding the accessibility of this scarcely reported moiety. Furthermore, a three-component cascade thiomethylative Friedel-Crafts reaction was discovered using BF 3 SMe 2 as a dual Lewis acid and thiomethyl source to afford interesting diarylmethane derivatives. Finally, the synthetic utility of these compounds was demonstrated through the strategic use of the thiomethyl moiety as a latent leaving group in the synthesis of challenging unsymmetrical triarylmethanes. The work described herein serves to further highlight the utility of BF 3 SMe 2 as a convenient and multifaceted reagent/ reactant with applications reaching beyond standard ether deprotections.
■ EXPERIMENTAL SECTION General Information. Analytical thin-layer chromatography was performed on silica gel 60 F-254 plates and visualized with UV light. Flash column chromatography was performed on silica gel 60 (40−63 μm). 1 H and 13 C spectra were recorded at 400 and 100 MHz, respectively. The chemical shifts for 1 H NMR and 13 C NMR are referenced to Tetramethylsilane via residual solvent signals (1H: CDCl 3 at 7.26 ppm and DMSO-d 6 at 2.50 ppm; 13 C: CDCl 3 at 77.16 ppm and DMSO-d 6 at 39.52 ppm). Analytical high-performance liquid chromatography/ electrospray ionization (ESI)-mass spectrometry was performed using ESI and a C18 column (50 × 3.0 mm 2 , 2.6 μm particle size, 100 Å pore size) with CH3CN/H2O in 0.05% aqueous HCOOH as mobile phase at a flow rate of 1.5 mL/min. LC purity analyses were run using a gradient of 5−100% CH 3 CN/ H 2 O in 0.05% aqueous HCOOH as mobile phase at a flow rate of 1.5 mL/min for 5 min unless otherwise stated on a C18 column. High-resolution molecular masses (HRMSs) were determined on a mass spectrometer equipped with an ESI source and time-of-flight unless otherwise stated.
General Procedure A for Synthesis of Compounds 1b− 15b and 12ab. An oven-dried vial was charged with 0.5 mmol aldehyde. 1,2-Dichloroethane (DCE) (1 mL) was added, followed by 4 equiv (4 mmol, 0.42 mL) BF 3 SMe 2 . The vial was sealed, and the mixture was heated to 80°C. After 16 h, the mixture was cooled to 0°C and carefully quenched with 0.5 mL MeOH. The mixture was taken up in 20 mL DCM and poured into a separatory funnel. 10 mL Sat. Na 2 CO 3 was added and the phases were separated. The aqueous phase was extracted with an additional 2 × 20 mL DCM. The organics were pooled, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude material was purified over silica.
General Procedure B for Synthesis of Compounds 1d− 20d. A vial was charged with 0.5 mmol aldehyde and 1.1 equiv (0.55 mmol) nucleophile. DCE (1 mL) was added, followed by 4 equiv (2 mmol, 0.21 mL) BF 3 SMe 2. The vial was sealed and the mixture was heated to 80°C. After 16 h, the mixture was cooled to 0°C and the reaction was quenched with 0.2 mL water. The mixture was poured into 10 mL sat. Na 2 CO 3 and extracted with 3 × 20 mL DCM. The organics were pooled, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude material was purified over silica.
General Procedure C for Synthesis of Compounds 1g− 1i. A vial was charged with 77.2 mg (0.3 mmol) 1d and 2 equiv (0.6 mmol) nucleophile. AcOH (1 mL) was added, and the mixture was heated to 120°C for 1 h with the vial open to the atmosphere. The mixture was cooled to ambient temperature and poured into 10 mL sat. Na 2 CO 3 and extracted with 3 × 20 mL DCM. The organics were pooled, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure. The resulting crude material was purified over silica.